There is a global urgency to develop a protective vaccine against HIV-1. Although neutralizing Abs (nAbs) can provide effective prophylaxis against HIV-1 acquisition, eliciting those that are broadly reactive against many antigenically diverse HIV-1 isolates has been a major challenge and it remains a critical roadblock for AIDS vaccine development. The primary objective of this exploratory R21 application is to explore a novel vaccine strategy to elicit strong Ab responses against the CD4 binding site (CD4BS) of HIV-1 gp120 with an eventual goal of inducing broadly neutralizing Abs (bnAbs). This will be accomplished by using antigens complexed with specific monoclonal Abs (mAbs) with defined epitopes to mask immunogenic epitopes that induce non-neutralizing Abs and focus immune responses towards the CD4BS. The underlying principle behind this application is that the immunogenicity of antigens can be altered when they are bound to Abs. Furthermore, how it is altered is determined by where the Abs bind. At present, the functional relationship between B cell epitopes on gp120 and Ab's ability to alter humoral responses has not been fully delineated. Better understanding of this relationship could provide new insights towards developing more effective vaccine strategies. The specific hypotheses to be tested are: (1) the induction of non-neutralizing or strain-specific neutralizing Abs can be avoided or minimized by masking the epitopes using mAbs that bind to the very same epitopes; and (2) blocking highly immunogenic non-/strain-specific neutralizing epitopes, while leaving the CD4BS fully exposed, would force the immune system to focus Ab responses towards it; this would result in greater levels of CD4BS Abs, some of which could be broadly neutralizing. The major innovations/strengths of our proposal are: (1) extensive experience in evaluating immunogenicity of HIV-1 antigens in rabbits; (2) a large library of rabbit mAbs, which will allow us to test the hypotheses in rabbits; (3) preliminary data demonstrating proof-of-principle that immune-masking can suppress Ab responses^ (4) the usage of multiple mAbs to mask all (or most) non-/strain-specific neutralizing epitopes, while allowing VRC01 to bind; and (5) the usage of low-pH sensitive mAbs that will release antigens in lysosomes for efficient antigen processing. Successful completion of proposed experiments would represent a major milestone towards development of a protective AIDS vaccine.